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Background: Depression is overrepresented in psoriasis. However, it is not clear whether the presence of psoriatic arthritis (PsA) independently increases patients' depressive burden. Furthermore, current evidence regarding suicidality risk of psoriasis populations is conflicting, and the role of PsA in suicidality outcomes of psoriasis is unknown. Objectives: (i) To test whether PsA is associated with depression and lifetime suicidal ideation among patients with psoriasis; (ii) to capture different suicidal phenomena in these patients; and (iii) to investigate whether suicidality and depressive symptom severity are associated with clinical markers of psoriasis severity and chronicity. Methods: A cross-sectional survey of tertiary patients (n = 219, aged 18–65 years) with dermatologist-confirmed chronic plaque psoriasis, of whom 84 had rheumatologist-confirmed PsA, was undertaken. The Hospital Anxiety and Depression Scale and Sheehan-Suicidality Tracking Scale were used to assess depression and lifetime suicidality, respectively. Results: PsA presence was associated with depression in patients with psoriasis, independent of other physical comorbidities (adjusted odds ratio 2.92, 95% confidence interval 1.53–5.68). Furthermore, patients with PsA experienced significantly higher levels of anhedonia and anxiety, after controlling for psychiatric history. Of all participants, 48.8% reported lifetime suicidal ideation with or without intent, 21.3% reported suicidal planning, and 9.4% reported suicide attempts. Lifetime suicidality prevalence did not differ between patients with and without PsA. Depressive symptom severity and lifetime suicidality scores were not associated with objective measures of psoriasis severity or treatment group. Conclusions: These data suggest that joint involvement in psoriasis is associated with higher depressive burden. There is a need for routine depression screening among patients with psoriasis, particularly when PsA is present. Anhedonia appears to be a particularly relevant symptom in the depression phenotype of this population. We did not find a statistically significant association between PsA and suicidality. Nevertheless, suicidality rates in tertiary patients with psoriasis appear to be higher than those in the general population. Suicidality monitoring is recommended to help in reducing future psychiatric morbidity and mortality in patients with psoriasis.

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min−1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), which is upregulated in activated microglia, is a method for investigating whether immune activation is evident in the brain of adults with schizophrenia. This study aimed to measure TSPO availability in the largest patient group to date, and to compare it between patients with recent onset (ROS) and established (ES) schizophrenia. In total, 20 ROS patients (14 male), 21 ES (13 male), and 21 healthy controls completed the study. Patients were predominantly antipsychotic-medicated. Participants underwent a PET scan using the TSPO-specific radioligand [11C](R)-PK11195. The primary outcome was binding potential (BPND) in the anterior cingulate cortex (ACC). Secondary outcomes were BPND in six other regions. Correlations were investigated between TSPO availability and symptom severity. Data showed that mean BPND was higher in older (ES and controls) compared with younger (ROS and controls) individuals, but did not significantly differ between ROS or ES and their respective age-matched controls (ACC; ANOVA main effect of diagnosis: F1,58 = 0.407, p = 0.526). Compared with controls, BPND was lower in antipsychotic-free (n = 6), but not in medicated, ROS patients. BPND in the ES group was negatively correlated with positive symptoms, and positively correlated with negative symptom score. Our data suggest ageing is associated with higher TSPO but a diagnosis of schizophrenia is not. Rather, subnormal TSPO levels in drug-free recent-onset patients may imply impaired microglial development and/or function, which is counteracted by antipsychotic treatment. The development of novel radioligands for specific immune-mechanisms is needed for further clarification.

Psoriasis is a systemic, relapsing, inflammatory disease associated with serious comorbidities including mood problems and/or unhealthy lifestyle behaviours. Cutaneous and systemic abnormalities in innate and acquired immunity play a role in its pathogenesis. The exact pathogenetic mechanism remains elusive. Evidence is accumulating that TNF-alpha, IL-17 and IL-23 signalling are highly relevant as targeting these pathways reduces disease activity. Evidence suggests a strong link between psoriasis and depression in adults. The International Psoriasis Council (IPC) held a roundtable event, “Psoriasis and Mental Health”, in Barcelona, Spain which focused on the presence of depression and suicidality, plus the role of neuroinflammation in psoriasis, sleep disruption and the impact of depression on cardiovascular disease outcomes. We summarize here the expert presentations to provide additional insight into the understanding of psychiatric comorbidities of psoriasis and of the impact of chronic, systemic inflammation on neuro- and cardiovascular outcomes. the associations between psoriasis and other psychiatric comorbidities are still controversial and warrant further attention.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis. ispartof: JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM vol:40 issue:8 pages:1576-1585 ispartof: location:United States status: published

These guidelines from the British Association for Psychopharmacology address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting, involving experts in schizophrenia and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from the participants and interested parties, and cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. The practice recommendations presented are based on the available evidence to date, and seek to clarify which interventions are of proven benefit. It is hoped that the recommendations will help to inform clinical decision making for practitioners, and perhaps also serve as a source of information for patients and carers. They are accompanied by a more detailed qualitative review of the available evidence. The strength of supporting evidence for each recommendation is rated.

A number of effective maintenance medication options exist for bipolar disorder (BD) and these are regarded as the foundation of long-term treatment in BD. However, nonadherence to medication is common in BD. For example, a large data base study in the United States of America (USA) showed that approximately half of patients with BD were nonadherent with lithium and maintenance medications over a 12 month period. Such nonadherence carries a high risk of relapse due to the recurrent nature of the illness and the fact that abrupt cessation of treatment, particularly lithium, may cause rebound depression and mania. Indeed, medication nonadherence in BD is associated with significantly increased risks of relapse, recurrence, hospitalization and suicide attempts and a decreased likelihood of achieving remission and recovery, as well as with higher overall treatment costs. Factors associated with nonadherence include adverse effects of medication, complex medication regimens, negative patient attitudes to medication, poor insight, rapid-cycling BD, comorbid substance misuse and a poor therapeutic alliance. Clinicians should routinely enquire about nonadherence in a nonjudgmental fashion. Potential steps to improve adherence include simple pragmatic strategies related to prescribing including shared decision-making, psychoeducation with a clear focus on adherence, reminders (traditional and digital), potentially using a depot rather than an oral antipsychotic, managing comorbid substance misuse and improving therapeutic alliance. Financial incentives have been shown to improve adherence to depot antipsychotics, but this approach raises ethical issues and its long-term effectiveness is unknown. Often a combination of approaches will be required. The strategies that are adopted need to be patient specific, reflecting that nonadherence has no single cause, and chosen by the patient and clinician working together.

Positron emission tomography (PET) imaging of the 18kDa translocator protein (TSPO) has been used to investigate whether microglial activation, an indication of neuroinflammation, is evident in the brain of adults with schizophrenia. Interpretation of these studies is confounded by potential modulatory effects of antipsychotic medication on microglial activity. In the first such study in antipsychotic-free schizophrenia, we have used [11C](R)-PK11195 PET to compare TSPO availability in a predominantly antipsychotic-naïve group of moderate-to-severely symptomatic unmedicated patients (n=8), similarly symptomatic medicated patients with schizophrenia taking risperidone or paliperidone by regular intramuscular injection (n=8), and healthy comparison subjects (n=16). We found no evidence for increased TSPO availability in antipsychotic-free patients compared to healthy controls (mean difference 4%, p=0.981). However, TSPO availability was significantly elevated in medicated patients (mean increase 88%, p=0.032) across prefrontal (dorsolateral, ventrolateral, orbital), anterior cingulate and parietal cortical regions. In the patients with schizophrenia, TSPO availability was also strongly correlated with negative symptoms measured using the Positive and Negative Syndrome Scale across all the brain regions investigated (r=0.651-0.741). We conclude that the pathophysiology of schizophrenia is not associated with microglial activation in the 2-6 year period following diagnosis. The elevation in the medicated patients may be a direct effect of the antipsychotic, although this study cannot exclude treatment resistance and/or longer illness duration as potential explanations. It also remains to be determined whether it is present only in a subset of patients, represents a pro- or anti-inflammatory state, its association with primary negative symptoms, and whether there are significant differences between antipsychotics.

Positron Emission Tomography (PET) imaging has become an important tool to investigate brain function, such as the serotonin neurotransmitter system. The outcome of a PET study can, however, potentially be obscured by suboptimal and/or inconsistent choices made in very complex processing pipelines required to reach a quantitative estimate of radioligand binding. Variations in subject selection, experimental design, data acquisition, preprocessing, and data analysis may therefore lead to different neurobiological interpretations. In this article, we investigate the various approaches made by 21 different PET centres published in 105 original research articles in quantifying the cerebral serotonin transporter binding with [11C]DASB PET. Combinatorially, there are a total of 21 million different workflow possibilities. We highlight the remarkable variety of ways in which researchers are currently conducting their studies, while implicitly expecting generalizable results across research groups. This study provides powerful evidence that the importance of preprocessing pipelines and their experimental interactions seem to be an overlooked aspect in modern PET neuroscience, and we believe that such testing is necessary in order to reliably provide new insights into human brain function. The key findings provide insight into acquisition- and preprocessing differences in published [11C]DASB studies, thereby enforcing the need for transparency, reproducibility and standardization for future data sharing opportunities in the PET neuroimaging community.

Deep brain stimulation is a potential option for patients with treatment-refractory depression. Deep brain stimulation benefits have been reported when targeting either the subgenual cingulate or ventral anterior capsule/nucleus accumbens. However, not all patients respond and optimum stimulation-site is uncertain. We compared deep brain stimulation of the subgenual cingulate and ventral anterior capsule/nucleus accumbens separately and combined in the same seven treatment-refractory depression patients, and investigated regional cerebral blood flow changes associated with acute and chronic deep brain stimulation. Deep brain stimulation-response was defined as reduction in Montgomery–Asberg Depression Rating Scale score from baseline of ≥50%, and remission as a Montgomery–Asberg Depression Rating Scale score ≤8. Changes in regional cerebral blood flow were assessed using [15O]water positron emission tomography. Remitters had higher relative regional cerebral blood flow in the prefrontal cortex at baseline and all subsequent time-points compared to non-remitters and non-responders, with prefrontal cortex regional cerebral blood flow generally increasing with chronic deep brain stimulation. These effects were consistent regardless of stimulation-site. Overall, no significant regional cerebral blood flow changes were apparent when deep brain stimulation was acutely interrupted. Deep brain stimulation improved treatment-refractory depression severity in the majority of patients, with consistent changes in local and distant brain regions regardless of target stimulation. Remission of depression was reached in patients with higher baseline prefrontal regional cerebral blood flow. Because of the small sample size these results are preliminary and further evaluation is necessary to determine whether prefrontal cortex regional cerebral blood flow could be a predictive biomarker of treatment response.

Psoriasis is a chronic, immune-mediated inflammatory skin disease affecting approximately 2% of the population.1 It is associated with multiple comorbidities including arthritis, cardiovascular disease and the metabolic syndrome and as such is widely regarded as a systemic inflammatory condition.2 Depression is also overrepresented in psoriasis3 and may itself have a systemic inflammatory component to its aetiology.4 This article is protected by copyright. All rights reserved.

BACKGROUND: Major depressive disorder is associated with raised peripheral inflammatory markers. Mounting evidence also suggests that inflammation is involved in suicidal behavior. However, the involvement of inflammation in the brains of individuals with depression, and its association with suicidal ideation, needs further clarification. Translocator protein (TSPO), which is upregulated in activated glia (predominantly microglia), can be measured as an indication of neuroinflammation invivo using positron emission tomography and TSPO-specific radioligands. METHODS: We used [11C](R)-PK11195 positron emission tomography to compare TSPO availability in the anterior cingulate cortex (ACC), prefrontal cortex, and insula between 14 medication-free patients in a major depressive episode of at least moderate severity and 13 matched healthy control subjects. In a post hoc analysis, we also compared TSPO availability between patients with and without suicidal thoughts. RESULTS: Multivariate analysis of variance indicated significantly higher TSPO in patients compared with control subjects (p= .005). The elevation was of large effect size and significant in the ACC (p= .022, Cohen's d= 0.95), with smaller nonsignificant elevations in the prefrontal cortex (p= .342, Cohen's d= 0.38) and insula (p= .466, Cohen's d=0.29). TSPO was not elevated in patients without suicidal thinking but was significantly increased in those with suicidal thoughts compared with those without, most robustly in the ACC (p= .008) and insula (p= .023). CONCLUSIONS: We confirm evidence for increased TSPO availability, suggestive of predominantly microglial activation, in the ACC during a moderate to severe major depressive episode. Our findings provide further incentive for evaluating anti-inflammatory therapies in major depressive disorder.

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.

Introduction Scanning properties and analytic methodology of the 5-HT 2A receptor-selective positron emission tomography (PET) tracer 11 C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects. Methods 64 11 C-MDL100907 PET scans with metabolite-corrected arterial input function were performed in 39 healthy adults (18–55 years). 12 subjects were scanned twice (duration 150 min) to provide data on plasma analysis, model order estimation, and stability and test–retest characteristics of outcome measures. All other scans were 90 min duration. 3 subjects completed scanning at baseline and following 5-HT 2A receptor antagonist medication (risperidone or ciproheptadine) to provide definitive data on the suitability of the cerebellum as reference region. 10 subjects were scanned under reduced 5-HT and control conditions using rapid tryptophan depletion to investigate vulnerability to competition with endogenous 5-HT. 13 subjects were scanned as controls in clinical protocols. Pooled data were used to analyse the relationship between tracer injected mass and receptor occupancy, and age-related decline in 5-HT 2A receptors. Results Optimum analytic method was a 2-tissue compartment model with arterial input function. However, basis function implementation of SRTM may be suitable for measuring between-group differences non-invasively and warrants further investigation. Scan duration of 90 min achieved stable outcome measures in all cortical regions except orbitofrontal which required 120 min. Binding potential (BP P and BP ND ) test–retest variability was very good (7–11%) in neocortical regions other than orbitofrontal, and moderately good (14–20%) in orbitofrontal cortex and medial temporal lobe. Saturation occupancy of 5-HT 2A receptors by risperidone validates the use of the cerebellum as a region devoid of specific binding for the purposes of PET. We advocate a mass limit of 4.6 μg to remain below 5% receptor occupancy. 11 C-MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BP ND were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalisation. Mean age-related decline in brain 5-HT 2A receptors was 14.0 ± 5.0% per decade, and higher in prefrontal regions. Conclusions Our data confirm and extend support for 11 C-MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT 2A receptors in the human brain.

Iterative image reconstruction methods such as ordered-subset expectation maximization (OSEM) are widely used in PET. Reconstructions via OSEM are however reported to be biased for low-count data. We investigated this and considered the impact for dynamic PET. Patient listmode data were acquired in [(11)C]DASB and [(15)O]H(2)O scans on the HRRT brain PET scanner. These data were subsampled to create many independent, low-count replicates. The data were reconstructed and the images from low-count data were compared to the high-count originals (from the same reconstruction method). This comparison enabled low-statistics bias to be calculated for the given reconstruction, as a function of the noise-equivalent counts (NEC). Two iterative reconstruction methods were tested, one with and one without an image-based resolution model (RM). Significant bias was observed when reconstructing data of low statistical quality, for both subsampled human and simulated data. For human data, this bias was substantially reduced by including a RM. For [(11)C]DASB the low-statistics bias in the caudate head at 1.7 M NEC (approx. 30 s) was -5.5% and -13% with and without RM, respectively. We predicted biases in the binding potential of -4% and -10%. For quantification of cerebral blood flow for the whole-brain grey- or white-matter, using [(15)O]H(2)O and the PET autoradiographic method, a low-statistics bias of

ObjectiveTo investigate the relationship of in vivo microglial activation to clinical and MRI parameters in MS.MethodsPatients with secondary progressive MS (n = 10) or relapsing-remitting MS (n = 10) and age-matched healthy controls (n = 17) were studied. Microglial activation was measured using PET and radioligand [11C](R)-PK11195. Clinical assessment and structural and quantitative MRI including diffusion tensor imaging (DTI) were performed for comparison.Results[11C](R)-PK11195 binding was significantly higher in the normal-appearing white matter (NAWM) of patients with secondary progressive vs relapsing MS and healthy controls, in the thalami of patients with secondary progressive MS vs controls, and in the perilesional area among the progressive compared with relapsing patients. Higher binding in the NAWM was associated with higher clinical disability and reduced white matter (WM) structural integrity, as shown by lower fractional anisotropy, higher mean diffusivity, and increased WM lesion load. Increasing age contributed to higher microglial activation in the NAWM among patients with MS but not in healthy controls.ConclusionsPET can be used to quantitate microglial activation, which associates with MS progression. This study demonstrates that increased microglial activity in the NAWM correlates closely with impaired WM structural integrity and thus offers one rational pathologic correlate to diffusion tensor imaging (DTI) parameters.

INTRODUCTION OR BACKGROUND: Depression frequently fails to respond to initial treatment. SOURCES OF DATA: Predominantly meta-analyses and RCTs but supplemented where necessary by additional data and the authors' clinical experience. AREAS OF AGREEMENT: A systematic assessment to identify remedial causes of poor response should be followed by planned sequential treatment trials. Joint decision making by the patient and clinician is essential. Strategies with the strongest support are antidepressant augmentation with lithium or second generation antipsychotics and adding cognitive behavioural treatment. Electroconvulsive therapy is highly effective in resistant depression but there is a high relapse rate when treatment ends. AREAS OF CONTROVERSY: Some pharmacological strategies have inconsistent data (e.g. antidepressant combinations, T3 augmentation) or limited preliminary data (e.g. ketamine, antidepressant augmentation with pramipexole). The efficacy of vagus nerve stimulation, deep brain stimulation and repetitive transcranial magnetic stimulation is unclear. GROWING POINTS: A greater understanding of the causes of depression may assist the development of more effective treatments. AREAS TIMELY FOR DEVELOPING RESEARCH: Role of glutamate antagonists and psychological treatments, other than cognitive behavioural therapy, as adjunctive treatments.

Quantitative non-invasive imaging of target structures in the human central nervous system provided by positron emission tomography (PET) permits investigation of the relationship between molecular events and pharmacological effects in living humans. Due to their prominent role in opiate and stimulant drug misuse and dependence, as well as in nociceptive signaling, µ- and κ-opioid receptors are potential targets for advances in neuro(psycho)pharmacological treatment of these illnesses and syndromes. In this review, we describe recent developments in specific positron emitting radiopharmaceuticals for these opioid receptor subclasses. Implications for further advances and clinical applications of the labeled ligands are discussed. Drug Dev. Res. 67:890–904, 2006. © 2007 Wiley-Liss, Inc.

In healthy humans, there is an apparent dissociation between cognitive and affective consequences of reduced brain serotonin (5-HT), as rapid tryptophan depletion (RTD) causes alterations in a consistent constellation of cognitive processes in the general absence of mood deterioration. This study aimed to investigate possible neural mechanisms underlying this relative dissociation by measuring the effects of reduced 5-HT on regional cerebral blood flow (rCBF). A total of 16 healthy, euthymic male subjects (mean age 39+/-9 years) without a personal or family history of affective disorder had mood ratings and single photon emission computed tomography scans with the rCBF tracer 99mTc-HMPAO under reduced 5-HT (RTD) and control conditions. Across individuals, modest positive and negative changes in subjective happiness associated with RTD were significantly correlated with change of rCBF in a cluster comprising subgenual (affective) anterior cingulate cortex (ACC) and associated regions (Brodmann's area (BA) 25, posterior BA11 and 47, caudate nucleus and ventral striatum; SPM99 p0.05, corrected). The covariation was such that increasing sadness was associated with increased rCBF and vice versa. Independent of mood change, RTD was associated with reduced rCBF in the dorsal (cognitive) ACC (BA32; SPM99 p0.05, corrected). The subgenual prefrontal cortex and dorsal ACC are important components of the ventral and dorsal neural systems that regulate and integrate affective and cognitive functions. The results therefore suggest that the dissociation between affective and cognitive consequences of RTD may possibly be attributable to differential effects of reduced 5-HT on these neural systems.

Background A decrease in dopamine type 2 receptors (D 2 ) and mesolimbic dopamine transmission predisposes animals to consume alcohol. This study measured D 2 receptors and dopamine transmission in human alcohol-dependent (AD) subjects using positron emission tomography (PET) and [ 11 C]raclopride. Methods Fifteen AD and 15 healthy control (HC) subjects were scanned before and after a psychostimulant challenge (amphetamine .3 mg/kg intravenous). The outcome measures for baseline D 2 receptor availability were binding potential (BP) and the equilibrium partition coefficient (V 3 ″). Amphetamine-induced [ 11 C]raclopride displacement was measured as the difference in V 3 ″ between the two scans. Results [ 11 C]raclopride BP was significantly reduced by 16.6% in the limbic striatum, 19.2% in the associative striatum, and 21.3% in the sensorimotor striatum in AD subjects compared with HC. The alcohol-dependent subjects showed a blunting of amphetamine-induced dopamine release in the limbic striatum: [ 11 C]raclopride displacement was −5.2% ± 3.6% in AD subjects compared with −13.0% ± 8.8% in HC. However, no significant difference in [ 11 C]raclopride displacement was seen in the associative (−4.6% ± 5.8% in AD subjects vs. −6.7 ± 5.4% in HC) and sensorimotor (−12.3% ± 7.3% in AD subjects vs. −13.7 ± 7.5% in HC) subdivisions of the striatum between the two groups. Conclusions Alcohol dependence was associated with a decrease in D 2 receptors in each striatal subdivision, whereas amphetamine-induced dopamine release was reduced in the limbic striatum only.

OBJECTIVE: The serotonin system is believed to play a role in modulating impulsivity and violence. Previous imaging studies have implicated the anterior cingulate and orbitofrontal cortex in impulsive aggression. This study evaluated regional serotonin transporter distribution in the brain of individuals with impulsive aggression by using positron emission tomography (PET) with the serotonin transporter PET radiotracer [(11)C]McN 5652. METHOD: Ten individuals with impulsive aggression and 10 age- and sex-matched healthy comparison subjects underwent [(11)C]McN 5652 PET. All individuals were medication free at the time of scanning. Regional total distribution volumes were derived by using a one-tissue compartment kinetic model with arterial input function. Outcome measures of serotonin transporter availability included the binding potential and the specific-to-nonspecific partition coefficient (V(3)''). RESULTS: Serotonin transporter availability was significantly reduced in the anterior cingulate cortex of individuals with impulsive aggression compared with healthy subjects, as noted by differences in both binding potential (mean=3.1 ml/g [SD=1.9] versus 5.0 ml/g [SD=2.0], respectively) and V(3)'' (mean=0.15 [SD=0.09] versus 0.26 [SD=0.09]). In other regions examined, serotonin transporter density was nonsignificantly lower in individuals with impulsive aggression compared with healthy subjects. CONCLUSIONS: Pathological impulsive aggressivity might be associated with lower serotonergic innervation in the anterior cingulate cortex, a region that plays an important role in affective regulation.

This paper reviews the molecular neuroimaging of anxiety disorders, and attempts to put recent advances in the context of previous findings. Knowledge of the metabolic correlates of symptom severity and treatment response in obsessive-compulsive disorder has been significantly extended, particularly response to selective serotonin reuptake inhibitor medication. However, the first neuroreceptor studies of serotonin transporter availability in obsessive-compulsive disorder have proved inconclusive, and further studies are anticipated. Reduced 5-HT1A receptor binding has been reported in panic disorder. Recent findings have extended the knowledge of hippocampal abnormalities in post-traumatic stress disorder, and have highlighted the complexity of the association between cortisol and the hippocampus in this disorder.

(-)-N-Propyl-norapomorphine (NPA) is a full dopamine (DA) D 2 receptor agonist and [ 1 1 C]NPA is a suitable radiotracer to image D 2 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study the vulnerability of the in vivo binding of [ 1 1 C]NPA to acute fluctuation in synaptic DA was assessed with PET in baboons and compared to that of the reference D 2 receptor antagonist radiotracer [ 1 1 C]raclopride. Three male baboons were studied with [ 1 1 C]raclopride and [ 1 1 C]NPA under baseline conditions and following administration of the potent DA releaser amphetamine (0.3, 0.5, and 1.0 mg kg - 1 i.v.). Kinetic modeling with an arterial input function was used to derive the striatal specific-to-nonspecific equilibrium partition coefficient (V 3 "). [ 1 1 C]Raclopride V 3 " was reduced by 24 ′ 10%, 32 ′ 6%, and 44 ′ 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg - 1 , respectively. [ 1 1 C]NPA V 3 " was reduced by 32 ′ 2%, 45 ′ 3%, and 53 ′ 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg - 1 , respectively. Thus, endogenous DA was more effective at competing with [ 1 1 C]NPA binding compared to [ 1 1 C]raclopride binding, a finding consistent with the pharmacology of these tracers (agonist vs. antagonist). These results also suggest that 71% of D 2 receptors are configured in a state of high affinity for agonists in vivo. In conclusion, [ 1 1 C]NPA might provide a superior radiotracer to probe presynaptic DA function with PET in health and disease.

[(18)F]fallypride is a new positron emission tomography (PET) dopamine D(2) receptor radiotracer that provides visualization of D(2) receptors in both striatal and extrastriatal areas. Here, the vulnerability of [(18)F]fallypride binding to endogenous dopamine (DA) levels was evaluated by examining the effect of amphetamine on [(18)F]fallypride binding in striatal and extrastriatal regions. Data were acquired in three male baboons at three different doses of i.v. amphetamine, using two different [(18)F]fallypride administration protocols (single bolus and bolus plus constant infusion). Scans were performed following a single bolus of [(18)F]fallypride under control conditions and following 1 mg/kg i.v. amphetamine and with an [(18)F]fallypride bolus plus constant infusion design under control, 0.5 mg/kg, and 0.3 mg/kg amphetamine i.v. conditions. Significant decreases in [(18)F]fallypride binding potential were seen in striatum (-49%, -18%, and -14%), thalamus (-25%, -23%, and -14%), and hippocampus (-36%, -24%, and -12%) following 1 mg/kg, 0.5 mg/kg, and 0.3 mg/kg doses of amphetamine, respectively. Additional analyses were performed suggesting that these results were not artifacts of nonreceptor-related effects such as regional flow changes or partial volume effects. In conclusion, [(18)F]fallypride binding is vulnerable to endogenous competition by DA in striatum as well as extrastriatal regions, suggesting that this ligand may be suitable for the study presynaptic DA function in striatal and extrastriatal areas.

We reviewed findings from PET and SPECT studies that have contributed to our understanding of the pathophysiology and treatment of schizophrenia. The most robust set of findings pertains to imaging of presynaptic dopaminergic function in the striatum. The results of these studies have been consistent in showing that schizophrenia, at least during episodes of illness exacerbation, is associated with increased activity of DA neurons; this increased presynaptic activity is associated with positive symptoms and good therapeutic response. Studies of cortical DA function are less numerous and less consistent. In the future, technical advances in PET instrumentation and radioligand development should contribute to a clarification of the role of prefrontal DA in the cognitive impairment that is presented by these patients. An important drawback of the literature in this field is the generally low number of subjects that are included in studies (typically less than 20 per group). Small samples are necessitated by the cost of these investigations, but also, in some instances, to the difficulty in recruiting appropriate clinical subjects (such as drug-free patients who have schizophrenia). In conditions that are characterized by marked heterogeneity, such as major depressive disorders, this factor is bound to yield divergent results across studies. Another source of discrepancy is the variety of technical approaches to data acquisition and analysis. For example, analytical methods range from "empirical" or "semiquantitative" (typically a region of interest to a region of reference ratio measured at one time point) to model-based methods that use an arterial input function. The limitations that are associated with empirical analytical methods might account for artifactual results, especially when the effect size of the between-group difference and the number of subjects are small [149]. In addressing these limitations it will be important to increase the availability of these techniques beyond a few academic centers, to promote multi-center studies in well-characterized populations, and to standardize analytical methods. Until recently, SPECT was the only widely available technique, and SPECT studies have provided a substantial contribution to this field. With the current increase in PET camera availability, the development of [18F]-based molecular imaging probes will provide unique opportunities for further dissemination of these techniques. The article reviewed seminal findings obtained with PET and SPECT molecular imaging of schizophrenia. These techniques do not play a major role in the diagnosis and treatment of this disorder, remain essentially research tools. The results that have been produced by this field to date suggest that PET will significantly contribute to unraveling the biologic bases of psychiatric disorders and may contribute to their clinical management. Moreover, it is foreseeable that PET will become increasingly involved in the development of new psychiatric medications. Expanding the availability of PET and the current radiopharmaceutical portfolio will be critical for these predictions to become reality.

This paper reviews the contribution of human PET and SPECT neuroreceptor occupancy studies to the understanding of drug action in psychiatric illness, and how they can aid the development of new drugs. All effective antipsychotics show significant D(2) receptor occupancy. However, at least for atypical antipsychotics, there is no clear relationship between occupancy and clinical response. The mechanisms underlying antipsychotic efficacy, and the minimal effective D(2) occupancy, remain to be elucidated, particularly for drugs with modest or transient occupancy. The low liability of some atypical antipsychotics for extrapyramidal side effects does not appear to be explained by their 5-HT(2A) antagonism, and the muscarinic receptor occupancy of some drugs may be partly explanatory. Previous reports of apparent 'limbic selectivity' of atypical antipsychotics may be in error, and may be due to technical differences in radiotracers. For SSRIs, high occupancies at the serotonin transporter (SERT) are achieved at therapeutic doses, although the minimum SERT occupancy required for therapeutic response remains undefined. Previous attempts to augment the antidepressant effect of SSRIs by pindolol have generally used daily doses which result in inadequate 5-HT(1A) receptor occupancy. For benzodiazepines, clinical doses would appear to leave a wide margin of unoccupied receptors. For methylphenidate and cocaine, typical doses occupy more than 50% of dopamine transporters, and their profiles are extremely similar. In therapeutic drug development, these techniques may be used to assess receptor occupancy profiles, likely drug dosages and dosing intervals which cannot be reliably assessed in humans by other methods.

Background Impulsive aggression (IA) in adults is associated with brain serotonin (5-HT) system abnormalities and is more common following childhood adversity. Within aggressive behavior, IA and callous unemotional (CU) traits are core components of differentiable factors with opposing 5-HT abnormalities. We aimed to investigate 5-HT abnormalities in IA and potential correlations with severity of childhood adversity while controlling for confounding 5-HT effects of high CU traits and mental disorders. Methods Healthy male subjects (mean age 34 ± 9 years) without high CU traits were recruited with IA ratings in the high ( n = 14) and low ( n = 13) population extremes. Serotonin transporter (SERT) and 5-HT 2A receptor availability was measured in multiple brain regions using positron emission tomography with 11 C-DASB and 11 C-MDL100907, respectively, and compared between high-IA and low-IA groups. Correlations were measured between SERT and 5-HT 2A receptor availability, impulsivity and aggression, and childhood adversity. Results Compared with the low-IA group, SERT were significantly higher in brainstem regions in the high-IA group (by 29.0% ± 11.4%) and modestly lower across cortical regions (by 11.1% ± 6.0%), whereas 5-HT 2A receptors were also modestly lower (by 8.6% ± 4.0%). Across all subjects, brainstem SERT were significantly positively correlated with impulsivity, aggression, and childhood trauma ratings. Within the high-IA group, higher brainstem SERT was most strongly predicted by severity of childhood trauma ( r = .76 in midbrain). Conclusions Pre-and postsynaptic 5-HT differences are present in men with high levels of IA and are strongly suggestive of a persisting effect of childhood adversity on serotonergic neurodevelopment and emotional-behavioral control.

Background Huntington’s disease (HD) is a neurodegenerative disease clinically characterised by progressive movement disorders, neuropsychiatric disturbances and cognitive impairment. Genetic testing enables us to investigate early changes in presymptomatic individuals carrying the abnormally expanded trinucleotide (CAG) repeat length on chromosome 4, who have not yet developed the characteristic motor disturbances of the disorder. Affective symptoms (depression and anxiety), irritability and apathy are the core psychiatric problems in presymptomatic HD but the pathophysiological substrate of these features in HD is not well understood. There is emerging evidence that depression might be associated with peripheral and CNS inflammation. Of particular interest in this context is the role of activated microglia and their interaction with serotonin (5-HT) metabolism. Aims To assess the correlation between microglial activation, serotonin receptor (SERT) binding and affective symptoms in presymptomatic HD gene carriers with in vivo PET imaging. Methods 12 participants (male and female, age 18–60 years) with a positive predictive test for HD (CAG repeat length ≥36) who were found to show irritability or affective symptoms on the PBAs (Problem and Behaviour Assessment, short version) were recruited from the Genetic Medicine clinic at St Mary’s Hospital, Manchester. Participants did not yet have a clinical diagnosis (based on motor symptoms) of HD. Participants underwent detailed clinical, neuropsychological and neuropsychiatric assessments in a cross-sectional design. [11C](R)-PK11195 PET (imaging microglial activation) and [11C]DASB-PET (measuring SERT binding) were obtained following standard protocols on the high resolution HRRT PET camera that allows evaluation of small brain structures (including brainstem nuclei) and structural MRI. Results PET scanning has been concluded just before abstract submission, and the PK11195 and DASB PET are currently quantified. Regional binding potential (BP) values for both modalities are being correlated with clinical and affective parameters, and the results will be presented at the meeting. Funding European Huntington’s disease Network (EHDN), European Union’s Seventh Framework Program (FP7/2007-2013) under grant agreement no. HEALTH-F2-2011–278850, (INMiND)

Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15 mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. (11)C-DASB PET scans were performed on the HRRT camera. Binding potentials (BP(ND)) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30+/-10%), was similar across brain regions, but varied widely across subjects (15-46%). Occupancy was correlated positively (p=0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at

Ordered-subset expectation maximization (OSEM) is a widely used method of reconstructing PET data. Several authors have reported bias when reconstructing frames containing few counts via OSEM, although the level of bias reported varies substantially. Such bias may lead to errors in biological parameters as derived via dynamic PET. We examine low-statistics bias in OSEM reconstruction of patient data and estimate the subsequent errors in biological parameter estimates. Patient listmode data were acquired during a [11C]-DASB scan using a brain PET scanner, the high resolution research tomograph (HRRT). These data were sub-sampled to create many independent, low-count replicates. Each replicate was reconstructed with and without the use of an image based resolution model (PSF), from which bias and variance were calculated as a function of the noise equivalent counts (NEC). Time-activity curves were subsequently generated by Monte Carlo simulation and used to study the propagation of bias from the images into the biological parameters of interest, for which noise and bias were based on the NEC. The investigation was complemented by simulation of a PET scanner. Significant bias was observed when reconstructing data of low statistical quality, for both human and simulated data. For human data, this bias was substantially reduced by including a PSF model (e.g. caudate head, 1.7 M NEC, -5.5 % bias with PSF, -13 % bias without PSF). For the observed levels of bias, Monte Carlo simulations predicted biases in the binding potential of -4 and -10 % (with/without PSF). The use of the PSF changed the variance characteristics of the images, reducing variance at the voxel level for low to moderate numbers of iterations. We conclude that OSEM reconstruction of dynamic PET data can yield parameter estimates of acceptable accuracy (for DASB), despite producing biased images at low statistics. This is however dependent upon the application. The use of a resolution model is shown to reduce bias and is thus recommended. The most likely mechanism for this reduction is the suppression of noise. The magnitude of the bias for other tracers and methods of data analysis is yet to be evaluated.

Ketamine is a noncompetitive antagonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor that is used in human and animal medicine as an injectable anesthetic. The illegal use of ketamine as a recreational drug is rapidly growing. Very little is currently known about the consequences of repeated ketamine exposure in the human brain. Animal studies indicate that the prefrontal dopaminergic system is particularly vulnerable to the toxic effects of repeated administration of NMDA antagonists. In this study, dopamine D1 receptor availability was assessed by using positron emission tomography and the selective D1 receptor radioligand [11C]NNC 112 in a group of 14 recreational chronic ketamine users and matched healthy subjects.History of ketamine abuse was confirmed in subjects by hair analysis. [11C]NNC 112 binding potential was measured with kinetic analysis using the arterial input function.Dorsolateral prefrontal cortex D1 receptor availability was significantly up-regulated in chronic ketamine users ([11C]NNC 112 binding potential: mean=1.68 ml/g, SD=0.40) relative to comparison subjects (mean=1.35 ml/g, SD=0.35). No significant differences were noted in other cortical, limbic, or striatal regions. In the chronic ketamine user group, dorsolateral prefrontal cortex [11C]NNC 112 binding potential up-regulation was significantly correlated with the number of vials of ketamine (with a vial representing approximately 200-300 mg of ketamine) used per week.Chronic ketamine users exhibited a regionally selective up-regulation of D1 receptor availability in the dorsolateral prefrontal cortex, a phenomenon observed following chronic dopamine depletion in animal studies. These data suggest that the repeated use of ketamine for recreational purposes affects prefrontal dopaminergic transmission, a system critically involved in working memory and executive function.

Rapid tryptophan (Trp) depletion (RTD) has been reported to cause deterioration in the quality of decision making and impaired reversal learning, while leaving attentional set shifting relatively unimpaired. These findings have been attributed to a more powerful neuromodulatory effect of reduced 5-HT on ventral prefrontal cortex (PFC) than on dorsolateral PFC. In view of the limited number of reports, the aim of this study was to independently replicate these findings using the same test paradigms. Healthy human subjects without a personal or family history of affective disorder were assessed using a computerized decision making/gambling task and the CANTAB ID/ED attentional set-shifting task under Trp-depleted (n=17; nine males and eight females) or control (n=15; seven males and eight females) conditions, in a double-blind, randomized, parallel-group design. There was no significant effect of RTD on set shifting, reversal learning, risk taking, impulsivity, or subjective mood. However, RTD significantly altered decision making such that depleted subjects chose the more likely of two possible outcomes significantly more often than controls. This is in direct contrast to the previous report that subjects chose the more likely outcome significantly less often following RTD. In the terminology of that report, our result may be interpreted as improvement in the quality of decision making following RTD. This contrast between studies highlights the variability in the cognitive effects of RTD between apparently similar groups of healthy subjects, and suggests the need for future RTD studies to control for a range of personality, family history, and genetic factors that may be associated with 5-HT function.

Brain kappa-opioid receptors (ORs) may be involved in several pathologic conditions, such as addiction, psychosis, and seizures. (+/-)-4-Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine (GR89696) is a potent and selective kappa-OR agonist. The (-)-isomer, GR103545, is the active enantiomer of GR89696. The aim of this study was to characterize the potential of 11C-GR103545 to image kappa-OR in vivo with PET.Brain uptake of 11C-GR103545 was studied in baboons under control conditions and after blockade by naloxone (1 mg/kg intravenously). Uptake of the racemic 11C-GR89696 and of the inactive enantiomer (+)-11C-GR89696 was also evaluated. Regional total distribution volumes were derived using the arterial input function and a 2-tissue-compartment model.11C-GR103545 showed excellent brain penetration and uptake kinetics, with significant washout observed within the time frame of the PET experiment. Naloxone pretreatment did not affect cerebellar total distribution volume and reduced total distribution volume in other regions to a level comparable to that in the cerebellum. The regional pattern of 11C-GR103545 binding potential was consistent with the distribution of kappa-OR in primate brain, with highest levels observed in anterior cortical regions (prefrontal cortex and cingulate cortex) and striatum. In most regions, the specific-to-nonspecific equilibrium partition coefficient (V3'') ranged from 1 to 2, predicting reliable quantification. 11C-GR103545 V3'' values were approximately double the 11C-GR89696 V3'' values, whereas (+)-11C-GR89696 V3'' values were negligible, demonstrating the enantiomeric selectivity of the binding and the advantage of using the pure active enantiomer for PET studies.11C-GR103545 is a promising PET radiotracer for imaging the kappa-OR.

The ability of single photon emisssion computed tomography (SPECT) and positron emission tomography (PET) to image specific biomolecules in the living brain provides a unique tool for clinical researchers. Given this, it is not surprising that the use of neuroreceptor imaging techniques has become more widespread over the past decade. These tools are currently being used to study neurological and psychiatric disorders and to inform early‐stage drug development. The accurate derivation of receptor parameters from PET or SPECT brain activity data involves model‐based methodology. These models take into account the various sources comprising the total activity observed in the brain and fluctuations in the relative contributions from these sources over the time course of the scan. The goal of this chapter is to first present the theory underlying these models providing the reader with a conceptual framework for understanding this technique. Subsequently, we will discuss the specific methods used to generate the outcome measures from neuroreceptor studies in detail. Finally, the application of neuroreceptor imaging to the study of specific psychiatric illnesses will be reviewed.

Although abnormal serotonin (5-HT) function is implicated in a range of mental disorders, there is currently no method to directly assess 5-HT synaptic levels in the living human brain. The in vivo binding of some dopamine (DA) radioligands such as (11)C-raclopride is affected by fluctuations in endogenous DA, thus providing an indirect measure of DA presynaptic activity. Attempts to identify a serotonergic radiotracer with similar properties have proved unsuccessful. Here, we investigated in humans the effects of reduced synaptic 5-HT on the in vivo binding of the 5-HT transporter (SERT) radioligand (11)C-DASB, using Positron Emission Tomography (PET) and the rapid tryptophan depletion (RTD) technique. Eight (8) subjects (5M, 3F) were scanned with (11)C-DASB under control and reduced endogenous 5-HT conditions, in a within-subject, double-blind, counterbalanced, crossover design. Regional distribution volumes (V(T)) were calculated using kinetic modeling and metabolite-corrected arterial input function. (11)C-DASB specific binding was estimated as binding potential (BP) and specific to nonspecific equilibrium partition coefficient (V(")(3)), using the cerebellum as reference region. RTD caused small but significant mean reductions in (11)C-DASB V(T) (-6.1%) and BP (-4.5%) across brain regions, probably explained by a concomitant reduction in (11)C-DASB plasma free fraction (f(1)) of similar magnitude. No significant change in (11)C-DASB V(")(3) was observed between control and reduced 5-HT conditions. Nor was there a significant relationship between the magnitude of tryptophan depletion and change in BP and V(")(3) across individual subjects. These results suggest that (11)C-DASB in vivo binding is not affected by reductions in endogenous 5-HT.

[18F]Fallypride is a new and promising radiotracer, suitable for imaging D2 receptors with Positron Emission Tomography (PET) in both striatal and extrastriatal regions. The high signal to noise ratio of [18F]fallypride has been attributed to its high affinity for D2 receptors (K(D) of 0.03 nM, measured in vitro at room temperature).We sought to further characterize this tracer in terms of its in vivo affinity, possible affinity differences between brain regions and dependence of in vitro affinity on temperature.PET scans were performed in baboons over a wide range of concentrations to measure the in vivo K(D) of [18F]fallypride in striatal and extrastriatal regions. Several analytical approaches were used, including nonlinear kinetic modeling and equilibrium methods. Also, in vitro assays were performed at 22 and 37 degrees C.No significant differences in the in vivo K(D) were detected between regions. In vivo K(D) of [18F]fallypride was 0.22+/-0.05 nM in striatum, 0.17+/-0.05 nM in thalamus, and 0.21+/-0.07 nM in hippocampus. These values were intermediate between in vitro K(D) measured at 22 (0.04+/-0.03 nM) and 37 degrees (2.03+/-1.07 nM).The in vivo affinity of [18F]fallypride was not as high as previously estimated from in vitro values. This property might contribute to the favorable kinetic properties of the tracer. The in vivo affinity was similar between striatal and extrastriatal regions. This result indicates that the measured regional in vivo affinities of this tracer are not affected by putative regional differences in endogenous dopamine, and that [18F]fallypride is an appropriate tool to provide unbiased estimates of the occupancy of D2 receptors by antipsychotic drugs in striatal and extrastriatal regions.

(-)-N-(11)C-propyl-norapomorphine ((11)C-NPA) is a new dopamine agonist PET radiotracer that holds potential for imaging the high-affinity states of dopamine D(2)-like receptors in the living brain. The goal of this study was to develop and evaluate analytic strategies to derive in vivo (11)C-NPA binding parameters.Two baboons were scanned 4 times after (11)C-NPA injections. The metabolite-corrected arterial input functions were measured. Regional brain time-activity curves were analyzed with kinetic and graphical analyses, using the arterial time-activity curve as the input function. Data were also analyzed with the simplified reference-tissue model (SRTM) and graphical analysis with reference-region input.(11)C-NPA exhibited moderately fast metabolism, with 31% +/- 5% of arterial plasma concentration corresponding to the parent compound at 40 min after injection. Plasma clearance was 29 +/- 1 L/h, and plasma free fraction (f(1)) was 5% +/- 1%. For kinetic analysis, a 1-tissue compartment model (1TCM) provided a good fit to the data and more robust derivations of the tissue distribution volumes (V(T), in mL/g) than a 2-tissue compartment model (2TCM). Using 1TCM, V(T)s in the cerebellum and striatum were 3.4 +/- 0.4 and 7.5 +/- 2 mL/g, respectively, which led to estimates of striatal binding potential (BP) of 4.0 +/- 1.1 mL/g and striatal equilibrium specific-to-nonspecific partition coefficient (V(3)") of 1.2 +/- 0.2. V(T) values derived with graphical analysis were well correlated with but slightly lower than V(T) values derived with kinetic analysis. V(3)" values derived with SRTM were well correlated with but slightly higher than V(3)" values derived with kinetic analysis. Using any method, a significant difference was detected in BP and V(3)" values between the 2 animals. It was determined that 30 min of scanning data were sufficient to derive V(3)" values using kinetic, graphical (arterial input and reference-region input), and SRTM analyses.This study indicates that (11)C-NPA is a suitable PET tracer to quantify the agonist high-affinity sites of D(2)-like receptors.

Eating behaviour, nutritional intake and psychopathology were examined in 16 weight-recovered anorexia nervosa patients. The Eating Disorders Examination (EDE) and a food diary were the main outcome measures, but body fat content and psychosocial adjustment were also assessed. Although body fat and overall psychosocial adjustment had returned to normal in most patients, 12 still had a restricted eating pattern with nutritional intake below 90% of their energy requirements. These results suggest that weight, menstruation, and psychosocial criteria are not sufficient to determine full recovery from anorexia nervosa, and that attention should be given also to measures of the specific behavioural and attitudinal disturbance.

Serotonin (5-HT) neurotransmission is involved in the normal regulation of affect and cognition, and its dysfunction is implicated in a range of mental disorders. However, there is currently no method to directly assess 5-HT synaptic levels in the living human brain. In the human dopamine (DA) system, baseline receptor occupancy by endogenous DA can be estimated by measuring the effects of DA depletion on the binding of certain radioligands through endogenous competition, particularly in striatum. For example, the measured increase in 11C-raclopride and 123I-IBZM binding following acute DA depletion implies a baseline D2 receptor occupancy of 10% in healthy humans. Brain 5-HT can be transiently and safely reduced by rapid tryptophan depletion (RTD), a technique involving the ingestion of an amino acid mixture lacking L-tryptophan, the dietary precursor of 5-HT. We have used RTD in healthy humans in an attempt to demonstrate a measurable effect of reduced 5-HT on the specific binding of the selective 5-HT transporter (SERT) ligand 11C-DASB and the selective 5-HT2A receptor antagonist ligand 11C-MDL100907. However, values of regional specific binding were not significantly different between the reduced endogenous 5-HT and control conditions for either tracer. These results suggest that PET with 11C-DASB or 11C-MDL100907 is not sensitive to the decreased concentration of synaptic 5-HT following RTD, and that neither tracer has the potential for measuring changes in synaptic levels of 5-HT in vivo. Imaging techniques relying on endogenous competition would ideally require a brain region with high synaptic levels of, and significant baseline receptor occupancy by, endogenous neurotransmitter. However, in vivo microdialysis studies in non-human primates suggest that extracellular 5-HT concentration is very low (< 0.5 nM) across brain regions and is 1 – 2 orders of magnitude lower than striatal DA levels. In the case of the 5-HT2A receptor, this concentration is significantly below the estimated KD of 5-HT for the receptor configured in a state of high affinity for agonists ( 1.3 nM). Moreover, in vitro studies suggest that the proportion of receptors configured in a state of high affinity for agonists, and therefore potentially available to endogenous 5-HT, is low ( 13%). Together, these values suggest that baseline occupancy of 5-HT2A receptors by 5-HT may be only approximately 2%, making changes following increased or decreased 5-HT unmeasurable by current techniques in humans. Agonist serotonergic radioligands may be expected to be superior for endogenous competition studies, but have so far been unsuccessful in humans. Efforts to experimentally increase baseline receptor occupancy (for example by pretreatment with selective 5-HT reuptake inhibitor medication) prior to RTD may be of interest. However, the insensitivity of current tracers to endogenous competition implies that they may be used to measure differences in SERT or 5-HT2A receptor availability between populations or during therapy without the need to consider concomitant changes in neurotransmitter concentration.